Simvastatin of formula (I) is a valuable hypocholesteremic drug, which inhibits biosynthesis of cholesterol by competitively inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase) thereby reducing the rate of formation of cholesterol in the human body. Simvastatin of formula (I) like its structurally similar analog lovastatin is active physiologically in the dihydroxylic acid form of formula (II) but is administered in the lactone form of formula (I).
                wherein R is hydrogen, NH4+ or an alkali metal        
The lactone form (I) is prepared by lactonization of the 3,5-dihydroxy acid derivative of formula (II) lactonization by various methods, which generally involves heating compound of formula (II) in the presence or absence of a bronsted acid or a dehydrating agent at various temperatures, employing various solvents.
Lactonization of the 3,5-dihydroxy pentanoic acid derivative of formula (II) is invariably accompanied by the formation of associated impurities especially the dimer impurity of formula (III) in variable amounts. This impurity is usually formed at higher temperature or in highly acidic conditions. Another impurity encountered during lactonization is the anhydro impurity (IV), which is formed in highly acidic conditions. These impurities are difficult to remove utilizing conventional methods of purification and if removed, considerably lower the yield of the product.

Prior art methods usually disclose the yield and purity of compound (I) but fail to mention any associated impurity such as the anhydro impurity of formula (IV) and the acetyl impurity (V), which could be formed during the reaction, when strong acids like methane sulfonic acid or a solvent like acetic acid is employed.
                wherein R is        

The minimization of the dimer impurity (III) is generally achieved by carrying out lactonization in a short duration or at a lower temperature or with dehydrating reagents like phosphorous pentoxide, molecular sieves etc which do not take part in the reaction.
The dimer impurity (III) is normally formed in reaction conditions, which are highly acidic or in concentrated solutions wherein there is a greater interaction between the substrate molecules. Therefore, prior art methods generally utilize high level of dilution of organic solvents between 40-50 times (w/w) per gram of the starting compound of formula (II) for controlling the level of impurities but in the process lactonization takes a longer time, between 20-60 hours for completion of reaction which consequently reduces the production capacity and increases the time cycle for each run.
Regulatory authorities all over the world are becoming very stringent about the level of impurities in an approved drug. Pharmacopoeial specification requires that the impurities such as the dimer impurity (III), anhydro impurity (IV) and acetyl impurity (V) in Simvastatin (I), which is difficult to remove by conventional methods, should be below 0.4%.
Needless to mention, most of the prior art methods do not give product conforming to the above mentioned criteria.
A brief summary of the prior art methods and their shortcomings has been already disclosed in our pending PCT Application PCT/IN04/00075, which describes an improved method for preparation of various compounds, which are structural analogues of simvastatin (I).
The method disclosed in PCT Application PCT/IN04/00075 is an improvement over the prior art methods and the invention residing in this application lies in the selection of a mixture of organic solvents viz. toluene and methyl ethyl ketone, temperature between 60-75° C., selection of catalyst, lower dilution of solvent which reduces reaction time and gives simvastatin of formula (I) of high purity, substantially free from impurities and conforming to pharmacopoeial specification.
The method disclosed in PCT Application PCT/IN04/00075 however requires a higher temperature (60-75° C.), a mixture of solvents viz. toluene and methyl ketone in a specific ratio (7:3). Further, Simvastatin (I) obtained by the above method also requires extensive purification for removal of associated impurities, since the dimer impurity (III) and the anhydro impurity (IV) (0.40% and 0.64% respectively) formed during lactonization are sufficiently high. Purification for removal of impurities lowers the yield to between 65-72%, therefore it is imperative to control these impurities during lactonization itself.
Therefore there exists a need for a method for manufacture of simvastatin of formula (I), which is simple, efficient and cost-effective but also gives simvastatin (I) in high yield and purity, substantially free of impurities.
It is therefore an object of the present invention to provide an improved process for preparation of simvastatin of formula (I) of high purity, with better yields and dimer purity (III) less than 0.05% and anhydro impurity of formula (IV) at less than 0.15%.
Another object of the invention is to provide an improved process for synthesis of simvastatin of formula (I) by agitating the corresponding 3,5-dihydroxy pentanoic acid derivative of formula (II) in a chlorinated solvent and in the presence of a weak acid like orthophosphoric acid at a temperature between 27-40° C. and in a short duration of 12-14 hours as compared to between 20-60 hours reported in prior art methods.
Yet another object of the invention relates to carrying out lactonization of the compound of formula (II) in a significantly lower dilution between 17 to 20 times (w/w) per gram of compound (II) and to give compound (I) of high purity and thereby making the process cost-effective.
It is a yet further object of the present invention to reduce the number of steps for isolating simvastatin (I) so as to conform to pharmacopoeial specification.
The present inventors have found that simvastatin of formula (I) can be synthesized from the 3,5-dihydroxy pentanoic acid derivative or its salt (II) by agitating in a chlorinated solvent for a period of 12-14 hours in the presence of a weak acid like orthophosphoric acid to give compound (I) of high purity, with dimer impurity (III) between 0.02% to 0.04% and which conforms to pharmacopoeial specification.
The present inventors further found that lactonization of compound of formula (II) can be achieved in a higher yield and purity through a method which utilizes a single solvent like a chlorinated solvent, at a lower temperature of 35±2° C. and utilizing an aqueous solution of an inorganic acid like orthophosphoric acid which not only reduces the dimer impurity of formula (III) below 0.05% but also reduces the formation of the anhydro impurity (IV) below 0.15%, during the lactonization reaction. Due to the low level of impurities formed during the reaction, extensive purification like prior art methods are not required thereby improving the yields.